The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior. It has also been implicated in the regulation of vascular tone, gut motility and cell-mediated immune responses. Walther, D. J., et al., Science 299:76 (2003). Serotonin also plays a role in clotting and hemostasis: platelets, which cannot themselves make serotonin, take up large amounts of peripheral 5-HT. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed., p. 274-5 (McGraw-Hill, 2001).
Serotonin is synthesized in two steps from the amino acid tryptophan. Goodman & Gilman's, p. 270. The first step is rate-limiting, and is catalyzed by the enzyme tryptophan hydroxylase (TPH), which has two known isoforms: TPH1, which is expressed in the periphery, and TPH2, which is expressed primarily in the brain. Walther, supra. The principle route by which serotonin is removed from the body involves the enzyme monoamine oxidase (MAO), which converts the compound to 5-hydroxyindole acetaldehyde, which is then converted to 5-hydroxyindole acetic acid (5-HIAA) by the enzyme aldehyde dehydrogenase. Goodman & Gilman's, p. 270-2.
Mice genetically deficient for the tph1 gene (“knockout mice”) have been reported. In one case, the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. Walther, supra. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. Côté, F., et al., PNAS 100(23):13525-13530 (2003). In a study directed at understanding the role of the enzyme in idiopathic pulmonary arterial hypertension, tph1 knockout mice were found to respond differently to the effects of hypoxia than wild type mice. Morecroft, I. et al., Hypertension 49:232-236 (2007).
Drugs that affect serotonin levels, such as MAO inhibitors and selective serotonin reuptake inhibitors (SSRIs)—which can inhibit platelets' ability to take up 5-HT—are often attended by adverse effects. A particularly severe example is the cardiotoxicity associated with the diet drug combination of fenfluramine and phentermine, known as “fen-phen,” which is believed to result from the combination's effect on the body's ability to control blood serotonin levels. MIT News Office, “Outdates [sic] label may have led to toxic combination of ‘fen-phen’” http://web.mit.edu/newsoffice/1998/fenphen-0902.html (1998).
Only recently have compounds developed for the safe and effective inhibition of TPH1 been disclosed. See U.S. patent application publication no. 2007-0191370. Such compounds allow for entirely novel approaches to treating, managing and preventing a wide range of diseases and disorders.